TMEM25 inhibits monomeric EGFR-mediated STAT3 activation in basal state to suppress triple-negative breast cancer progression

Jing Bi, Zhihui Wu, Xin Zhang, Taoling Zeng, Wanjun Dai, Ningyuan Qiu, Mingfeng Xu, Yikai Qiao, Lang Ke, Jiayi Zhao, Xinyu Cao, Qi Lin, Xiao Lei Chen, Liping Xie, Zhong Ouyang, Jujiang Guo, Liangkai Zheng, Chao Ma, Shiying Guo, Kangmei Chen, Wei Mo, Guo Fu (), Tong-Jin Zhao () and Hong-Rui Wang ()
Additional contact information
Jing Bi: Xiamen University
Zhihui Wu: Xiamen University
Xin Zhang: Xiamen University
Taoling Zeng: Xiamen University
Wanjun Dai: Xiamen University
Ningyuan Qiu: Xiamen University
Mingfeng Xu: Xiamen University
Yikai Qiao: Xiamen University
Lang Ke: Xiamen University
Jiayi Zhao: Xiamen University
Xinyu Cao: Xiamen University
Qi Lin: Xiamen University
Xiao Lei Chen: Cancer Research Center of Xiamen University
Liping Xie: Xiamen University
Zhong Ouyang: The First Affiliated Hospital of Xiamen University
Jujiang Guo: Xiamen University
Liangkai Zheng: Xiamen University
Chao Ma: Medical School of Chinese PLA
Shiying Guo: GemPharmatech Co., Ltd.
Kangmei Chen: Sun Yat-sen University
Wei Mo: Xiamen University
Guo Fu: Cancer Research Center of Xiamen University
Tong-Jin Zhao: Fudan University
Hong-Rui Wang: Xiamen University

Nature Communications, 2023, vol. 14, issue 1, 1-15

Abstract: Abstract Triple-negative breast cancer (TNBC) is a subtype of breast cancer with poor outcome and lacks of approved targeted therapy. Overexpression of epidermal growth factor receptor (EGFR) is found in more than 50% TNBC and is suggested as a driving force in progression of TNBC; however, targeting EGFR using antibodies to prevent its dimerization and activation shows no significant benefits for TNBC patients. Here we report that EGFR monomer may activate signal transducer activator of transcription-3 (STAT3) in the absence of transmembrane protein TMEM25, whose expression is frequently decreased in human TNBC. Deficiency of TMEM25 allows EGFR monomer to phosphorylate STAT3 independent of ligand binding, and thus enhances basal STAT3 activation to promote TNBC progression in female mice. Moreover, supplying TMEM25 by adeno-associated virus strongly suppresses STAT3 activation and TNBC progression. Hence, our study reveals a role of monomeric-EGFR/STAT3 signaling pathway in TNBC progression and points out a potential targeted therapy for TNBC.

Date: 2023
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DOI: 10.1038/s41467-023-38115-2

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